Orchestrating Stress Granule Dynamics by SUMOylation: A New Frontier in Treating Stress-Induced Age-Related Diseases

Stress granules (SGs), membrane-less organelles formed via liquid-liquid phase separation (LLPS), function as essential adaptive compartments that sequester mRNAs and proteins during acute stress. However, during chronic stress or aging, these dynamic condensates can undergo an irreversible phase transition into pathological insoluble aggregates, driving neurodegeneration and metabolic decline. The pivotal role of SUMOylation is elucidated as a molecular switch orchestrating the SG life cycle, from rapid nucleation and component recruitment to timely disassembly. The multivalent engagement of SUMO proteins and SUMO-interacting motifs (SIMs) is discussed as a biochemical glue that lowers the kinetic threshold for LLPS and maintains the fluid-like state of SG scaffold proteins. Furthermore, the dysregulation of the SUMO pathway, particularly the imbalance between E3 ligases and deSUMOylating enzymes, is examined in the context of cellular senescence, neurodegenerative proteinopathies, reproductive aging, and musculoskeletal degeneration. Emerging therapeutic strategies targeting the SUMO-SG axis are evaluated, including the clinical-stage inhibitor TAK-981, selective SUMO-specific proteases modulators such as Momordin Ic, and multi-target natural products. By decoding how the SUMO code biophysically governs cellular resilience, this review highlights the potential of state-corrective interventions to restore proteostasis and extend healthspan in stress-associated aging disorders.